ALKBH5 regulates STAT3 activity to affect the proliferation and tumorigenicity of osteosarcoma via an m6A-YTHDF2-dependent manner.
ALKBH5 regulates STAT3 activity to affect the proliferation and tumorigenicity of osteosarcoma via an m6A-YTHDF2-dependent manner.
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ALKBH 5通过m6 A-YTHDF 2依赖性方式调节STAT 3活性以影响骨肉瘤的增殖和致瘤性。
DOI：
10.1016/j.ebiom.2022.104019
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发表时间：
2022-06
期刊：
影响因子：
11.1
通讯作者：
Bao, Xing
中科院分区：
文献类型：
--
作者：
Yang, Zechuan;Cai, Zhuo;Yang, Caihong;Luo, Zhengqiang;Bao, Xing
N6-甲基腺苷（m6 A）是最常见和最丰富的mRNA修饰，在许多生物学过程中起着至关重要的作用。然而，作为一个关键的RNA去甲基化酶，烷基化修复同源蛋白5（ALKBH 5）在人类骨肉瘤中的研究还没有得到很好的。本研究旨在探讨ALKBH 5介导的m6 A修饰及其在人骨肉瘤中的潜在机制。采用生物信息学分析和组织芯片技术检测ALKBH 5的表达及其与临床病理特征的关系。CCK-8法检测细胞增殖。TUNEL法和流式细胞术检测细胞周期和凋亡。最后，通过MeRIP实验、RNA测序、双荧光素酶报告基因实验、RNA pull-down实验和RNA稳定性实验研究ALKBH 5在人骨肉瘤中的调控机制。建立肿瘤异种移植模型用于体内实验。我们的数据显示ALKBH 5的低表达与骨肉瘤患者的总体生存率较差相关。通过ALKBH 5上调降低人骨肉瘤细胞中m6 A mRNA水平导致细胞增殖抑制、细胞凋亡和周期停滞。我们鉴定了STAT 3的负调节因子SOCS 3作为ALKBH 5介导的m6 A修饰的下游靶标。而m6 A修饰的SOCS 3 mRNA被YTHDF 2识别，从而促进SOCS 3的降解。从机制上讲，我们的数据显示ALKBH 5通过m6 A-YTHDF 2依赖性方式增加SOCS 3表达来灭活STAT 3通路。M6 A甲基化作为影响致瘤性和肿瘤进展的途径正在上升。我们的研究结果阐明了ALKBH 5介导的m6 A修饰在人骨肉瘤中的临床意义以及肿瘤增殖和生长的调控机制，表明ALKBH 5是治疗人骨肉瘤的潜在生物标志物。本研究得到了湖北省科学技术基金（批准号：2017 CFB 762）、同济医院基金（批准号：2201103013）和国家自然科学基金（批准号：82002849）的资助。
N6-methyladenosine (m6A) is the most common and abundant mRNA modification and it plays crucial roles in many biological processes. However, as a key RNA demethylase, alkylation repair homolog protein 5 (ALKBH5) has not been well studied in human osteosarcoma. The present study sought to explore ALKBH5-mediated m6A modification and the underlying mechanisms in human osteosarcoma. The expression of ALKBH5 and its correlation with clinicopathological features were examined by bioinformatics analysis and tissue microarrays. Cellular proliferation was detected by CCK8 assays. Cell cycle and apoptosis were analyzed by TUNEL and Flow cytometry assay. Finally, investigation of the regulatory mechanism of ALKBH5 in human osteosarcoma was performed by MeRIP assay, RNA-sequencing, dual luciferase reporter assay, RNA pull-down and RNA stability assay. Tumor xenograft models were established for in vivo experiments. Our data showed that low expression of ALKBH5 was associated with worse overall survival for osteosarcoma patients. Reducing m6A mRNA levels in human osteosarcoma cells through ALKBH5 up-regulation lead to cell proliferation inhibition, cell apoptosis and cycle arrest. We identified SOCS3, a negative regulator of STAT3, as a downstream target of ALKBH5-mediated m6A modification. And the m6A modified SOCS3 mRNA was recognized by YTHDF2, which promotes the decay of SOCS3. Mechanistically, our data revealed that ALKBH5 inactivated STAT3 pathway by increasing SOCS3 expression via an m6A-YTHDF2-dependent manner. M6A methylation is rising as a pathway affecting tumorigenicity and tumor progression. Our findings illuminate the clinical significance of ALKBH5-mediated m6A modification in human osteosarcoma and the regulatory mechanisms underlying tumor proliferation and growth, suggesting that ALKBH5 is a potential biomarker for treatment in human osteosarcoma. This work was supported by and Science and Technology foundation of Hubei, China (Grant No.2017CFB762); the Tongji hospital foundation (Grant No.2201103013); and the National Natural Science Foudation of China (No.82002849).
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影响因子：
9
作者：
Sorci M;Ianniello Z;Cruciani S;Larivera S;Ginistrelli LC;Capuano E;Marchioni M;Fazi F;Fatica A
通讯作者：
Fatica A
影响因子：
9
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影响因子：
64.5
作者：
Su R;Dong L;Li C;Nachtergaele S;Wunderlich M;Qing Y;Deng X;Wang Y;Weng X;Hu C;Yu M;Skibbe J;Dai Q;Zou D;Wu T;Yu K;Weng H;Huang H;Ferchen K;Qin X;Zhang B;Qi J;Sasaki AT;Plas DR;Bradner JE;Wei M;Marcucci G;Jiang X;Mulloy JC;Jin J;He C;Chen J
通讯作者：
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m(6)A mRNA甲基化调控CTNNB1促进肝母细胞瘤增殖
影响因子：
37.3
作者：
Liu, Li;Wang, Jing;Pan, Qiuhui
通讯作者：
Pan, Qiuhui
影响因子：
28.5
作者：
Jin, Dan;Guo, Jiwei;Su, Guoming
通讯作者：
Su, Guoming